17-31370205-A-T

Variant names:

• chr17-31370205-A-T
• rs2107359
• NM_001042492.3:c.8378-3808A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001042492.3(NF1):​c.8378-3808A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,012 control chromosomes in the GnomAD database, including 20,702 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (20702 hom., cov: 31)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.937
• Publications: 9 publications found

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

NF1 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.8378-3808A>T		intron_variant	Intron 57 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.8315-3808A>T		intron_variant	Intron 56 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.8378-3808A>T		intron_variant	Intron 57 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75642 AN: 151894 Hom.: 20694 Cov.: 31

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.528

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.498 AC: 75673 AN: 152012 Hom.: 20702 Cov.: 31 AF XY: 0.495 AC XY: 36803 AN XY: 74292

African (AFR) AF: 0.277 AC: 11493 AN: 41488

American (AMR) AF: 0.444 AC: 6784 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2369 AN: 3466

East Asian (EAS) AF: 0.353 AC: 1819 AN: 5158

South Asian (SAS) AF: 0.567 AC: 2732 AN: 4818

European-Finnish (FIN) AF: 0.604 AC: 6374 AN: 10554

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.621 AC: 42203 AN: 67940

Other (OTH) AF: 0.525 AC: 1107 AN: 2108

Alfa AF: 0.540 Hom.: 2921

Bravo AF: 0.475

Asia WGS AF: 0.441 AC: 1530 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.36
DANN	Benign	0.67
PhyloP100		-0.94
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2107359; hg19: chr17-29697223;